Uremia is a syndrome showing various clinical symptoms stemmed from dysfunctions of various organs and tissues, caused by the toxic components in the urine accumulated in the blood. Uremia occurs when urine cannot be excreted from the body due to failure of renal function irrespective of the primary disease. Uremia has a wide variety of clinical symptoms including gastrointestinal abnormalities such as anorexia, nausea, vomiting, stomatitis and enteritis; nervous system abnormalities such as apathy, unconcern, deterioration of memory, depressed state and coma; circulatory abnormalities such as anemia, erythropoietic disorders, hypertension, ischemic heart diseases, pericarditis and myocarditis; pigmentation; itching; skin abnormalities such as subcutaneous hemorrhage and so on. Uremia is caused by uremic substances accumulated in the blood. It is thought that there are several tens or more uremic substances at present, including, for example, methylguanidine, indole compounds, malondialdehyde, creatinine, β-aminoisobutyric acid, transketolase inhibitors, polyamines, lipolytic inhibitors, urea, and phenols (see, for example, Non-patent Literature 1).
However, it has not yet been clarified which substance, among these uremic substances, essentially participates in the onset of uremic symptoms. Further, although it has not been clarified whether uremia is caused by a single substance or by compound effect of a plurality of these substances, it is thought that the probability of the latter is higher. These facts clearly indicate the difficulty in therapy of uremia by drugs. Anyway, unless the uremic substances are excreted from the body or unless the blood levels of the uremic substances are lowered by an appropriate means, the patient with uremia will die. The therapeutic methods said to be effective for the treatment of uremia are kidney transplantation, dialysis and active carbon preparation treatment. The advantage of the therapeutic methods common to the latter two methods is that a plurality of uremic substances including unknown substances can be removed or diluted nonspecifically by a physical means. However, the methods have drawbacks described below.
Active carbon preparation is orally administered. The mechanism of action of the active carbon preparation is based on the adsorption of various uremic substances generated in digestive organs and excretion thereof from the body. Thus, although the active carbon preparation is called an oral drug, the therapy may be considered as a physical therapeutic method similar to the dialysis treatment described below. Since the active carbon preparation has drawbacks in that taking is not easy, it has a strong tendency to induce constipation, and so on, in addition to the limited therapeutic effect, the therapeutic method is not satisfactory at all.
Dialysis is said to be the most effective therapeutic method for uremia. In fact, by excreting uremic substances by dialysis treatment, the death of the patient due to the uremic substances can be avoided even if the kidney function has been abolished. However, complications by dialysis treatment have been recognized as new problems. For example, complications of long-term dialysis include anemia, renal osteodystrophy, stomach cancer, pericarditis, aluminum osteodystrophy, amyloidosis, crystal arthritis, multiple polycystic kidney and so on. There are also problems of poor QOL of the patients in social life due to the necessity to frequently go to dialysis facilities, and high cost which is a problem in medical economics.
A method called “internal dialysis” has been reported, in which nonprotein nitrogen is medicinally transferred to intestinal tract without a physical means (Patent Literature 1). This is a phenomenon that upon administration of a 15-keto-16-halogen-prostaglandin E2, serum creatinine (Cre) and blood urea nitrogen (BUN) in the blood are transferred to the intestinal tract together with water by enteropooling action (an action to accumulate water in the intestinal tract). However, since enteropooling is an action to accumulate water in the intestinal tract, it necessarily accompanies diarrhea, and the reporter also refers to this point. No matter how much the serum Cre value and BUN value in the blood are decreased, to perform this therapy which accompanies the physical exhaustion and the risk of dehydration due to diarrhea imposes a very heavy burden on the patients with chronic renal failure, so that it is not acceptable at all.
Accordingly, creation of a therapeutic method and therapeutic agent for uremia, free from the above-described problems is demanded.
Although uremia occurs with the progress of renal failure, both of these are syndromes which are separately defined as described below. Non-patent Literature 2 states “a wide variety of, and sometimes confused, terms are used for expressing the renal function and its deterioration”, and defines related terms to clearly distinguish the both. More particularly, it calls attention on the difference between the both stating “Renal failure is the state in which the renal function is decreased and the abnormalities (azotemia and decrease in the ability to concentrate urine) are maintained, and means the function level of the organ rather than a specific disease”, and “Uremia indicates the fact that urine exists in the blood” (see Non-patent Literature 2). Other technical books of nephrology also define and describe uremia and renal failure as different “syndromes” and not “names of diseases” (Non-patent Literature 3).
Renal failure is classified into two different syndromes, acute renal failure and chronic renal failure. Acute renal failure suddenly occurs, but in most cases, its renal function impairment is reversible. In fact, effective drugs and therapeutic methods have already existed, and, in many cases, the renal function of the patients may be restored to the normal state by merely removing the cause. On the other hand, as for chronic renal failure, it is difficult to clearly determine the time of onset thereof, and it slowly occurs over several months to several years. Further, the renal damage occurred is irreversible (see, for example, Non-patent Literature 4), and refractory to various drugs and therapeutic methods. Thus, therapy of uremia which occurs with the progress of chronic renal failure is especially important.
As the results of the studies so far using nephritis model animals or renal failure model animals, various prophylactic and therapeutic drugs for chronic renal failure or its primary disease have been found. Various drugs are now clinically used, for example, antiplatelet drugs such as dipyridamole, dilazep hydrochloride, trapidil and aspirin; and anticoagulants such as heparin and warfarin are used for glomerulonephritis; and thiazide diuretics, loop diuretics, angiotensin converting enzyme (ACE) inhibitors, and calcium antagonists such as diltiazem and verapamil are used for cases where the primary disease is essential hypertension. However, any of these is nothing more than a countermeasure which delays the progress of the state of renal failure such as deterioration of renal function and the like, and amelioration or disappearance of uremia by these drugs has not been reported at all.
Among the compounds of General Formula (I) in the present application, beraprost sodium disclosed in Patent Literature 2 has been reported to be effective for primary diseases of chronic renal failure. For example, in a glomerulonephritis model system, Utsunomiya et al. showed that onset of glomerulonephritis can be inhibited by administering beraprost sodium, before onset, to immune complex-induced glomerulonephritis mouse NZB/WF1 which spontaneously develops immune complex-induced glomerulonephritis, using as an index the effect to decrease the urinary excretion of albumin (Non-patent Literature 5). Similarly, Kushiro et al. showed, using rat glomerulonephritis models, that onset of nephritis was prevented by prophylactically administering beraprost sodium to the rats before administering the nephritis-inducing substance, in terms of the effect to decrease the urinary excretion of albumin (Non-patent Literature 6). Stier et al. showed that by administering beraprost sodium together with the supply of saline used as the stimulation inducing hypertension and with feeding of a special diet to the rats which spontaneously develops hypertension, the onset of glomerulonephritis was prevented, based on the urinary protein excretion and an image of the tissue of glomerulus (Non-patent Literature 7). Further, it has been reported that urinary microalbumin in patients with diabetic nephropathy was decreased by the administration of beraprost sodium (Non-patent Literature 8).
Further, there are reports about prostaglandin I2 derivatives (hereinafter also referred to as “PGI2 derivatives” for short) other than the compounds represented by General Formula (I). For example, it is known that cicaprost has an activity to reduce the renal function impairment in streptozotocin-induced diabetic nephropathy rats (Non-patent Literature 9) or the renal function impairment induced by uninephrectomy, high sodium loading and protein loading (Non-patent Literature 10). Similarly, in Thy-1-induced nephritis models, urinary protein is decreased by prophylactically administering iloprost which is a PGI2 derivative before the induction of nephritis (Non-patent Literature 11). Proteinuria is caused by the deterioration of barrier function to macromolecules in the kidney. Therefore, although proteinuria is a good index for examining the glomerulus function which is an aspect of the renal function, proteinuria does not directly determine the severity of uremia. Further, although proteinuria is a good index in early stage of glomerulonephritis, diabetic nephropathy and the like, it is no longer a good index in chronic renal failure because the filtering function to low molecular substances are decreased in chronic renal failure. Further, all of the above-described reports show the prophylactic effects of PGI2 derivatives because the PGI2 derivatives were administered before the onset of nephritis, and do not show the therapeutic effect. Still further, although the reports refer to renal function, they do not refer to or suggest amelioration of uremia at all.
As for the effects of the compounds represented by General Formula (I), there is a report in which rat renal failure models whose primary disease was the nephritis, prepared by administering an antibody to glomerular basement membrane were used (Patent Literature 3). In the report, it was shown that by administering a compound of the General Formula (I) recited in the present application after observing renal failure defined by higher creatinine and BUN, increase in the renal failure markers such as amount of urinary protein excretion, serum Cre value and BUN value was reduced when compared with a control group. Further, it has been reported that clinical administration of beraprost sodium reduced the decrease in renal function in the renal failure in conservative stage, which is indicated by decrease in the creatinine clearance or in the reciprocal of serum creatinine in patients with renal failure (Non-patent Literature 12). However, these reports do not contain any reference or suggestion about uremia or uremic symptoms.
Renal diseases include hemolytic uremic syndrome (HUS) caused by thrombotic microangiopathy. HUS literally shows uremia as its clinical symptom. Series et al. reported that, in one case of HUS, administration of iloprost which is one of the PGI2 derivatives was effective for the improvement of the serum Cre value which is a marker of renal failure (Non-patent Literature 13). However, HUS is a syndrome stemmed from the above-described easily recoverable acute renal failure which is a pathological condition utterly different from uremia in the patients with chronic renal failure whose body homeostasis is drastically impaired, in the resistance to drugs and therapeutic methods. Thus, this report is also totally silent about the applicability to the therapy of uremia in patients with chronic renal failure, which is a severer syndrome.
On the other hand, Siegler et al. reported that PGI2 does not have an activity to inhibit the progress of HUS (Non-patent Literature 14). Even about in vitro studies, there is a report which reports that the ability of vascular endothelial cells to produce PGI2 said to be related to onset of HUS is decreased (Non-patent Literature 15), and a report which reports that no change was observed on the ability to produce PGI2 (Non-patent Literature 16). That is, the pharmacological effect of PGI2 derivatives to HUS is still very unclear, and the above-mentioned Series et al. described that the above-mentioned one case was a very rare case, the relationship between HUS and PGI2 was still contradicting, and frankly concluded that further study was necessary. Anyway, even in HUS which has a better ability to recover the body homeostasis, the involvement of PGI2 is still unclear, and the effectiveness of PGI2 to the uremia of patients with chronic renal failure, whose ability to recover the body homeostasis is much poorer or who have no such an ability, is not expected at all.
As described above, deterioration or amelioration of uremic symptoms in the patients with chronic renal failure by the compounds represented by the General Formula (I), or even by PGI2 derivatives including those other than the compounds represented by the General Formula (I), has not been described at all.
On the other hand, in recent years, increase in the number of patients with chronic renal failure has become a big problem not only in human medicine but also in veterinary medicine. Pet animals such as dogs and cats can now receive highly nutritious diets and high veterinary services. As a result, pet animals came to have a long life similar to humans, and the number of patients suffering from an aging-associated disease or chronic disease which is difficult to cure are now being drastically increased. Chronic renal failure is observed in many kinds of pet animals. Taking cat as an example, comparisons between the chronic renal failure of cats and humans are as follows:
In cats, chronic renal failure occurs at an especially high rate (see, for example, Non-patent Literature 17). In cats of not younger than 15 years old, chronic renal failure amounts to as much as 30% of total diseases, and is a major cause of death of cats (see, for example, Non-patent Literature 18). Further, in very many cases, when a patient cat is carried in an animal hospital, the cat is in considerably progressed state of chronic renal failure, and accompanies uremia.
In general, chronic renal failure of cats is diagnosed by detecting high values of serum creatinine (Cre) and blood urea nitrogen (BUN) value which are clinical markers of renal function, in addition to the past history obtained by hearing and the clinical observations. Abnormal Cre and BUN values are not detected unless 75% of nephron in both kidneys lost its function, and there is a correlation between the magnitude of the abnormal values of the markers of renal function and the ratio of remaining renal function, as in the case of humans.
Uremic symptoms of cats are expressed by nausea, vomiting, diarrhea, anorexia, weight loss, decreased activity, polydipsia and diuresis, intraoral ulcer and so on. Anorexia and shortage of water intake due to the intraoral ulcer also cause dehydration and constipation. After further progress of the diseased state, in addition to anemia, erythropoietic disorders, loss of appetite and depressed state, encephalopathy and neuropathy due to the urine toxin are observed. As described above, the progress of the diseased state of the chronic renal failure and the diversity of the accompanied uremic symptoms are the same as in humans.
Since the cats having progressed uremia tend to develop dehydration, as symptomatic treatments, hydration, and fluid replacement by intravenous or subcutaneous drip infusion for the purpose of dilution of the uremic substances are also performed. For anemia in cats with uremia, erythropoietin having hematopoietic activity is also administered. Since appetite is often reduced also by anemia, an appetite-stimulating treatment is also performed in parallel. For the amelioration of symptoms such as vomiting, diarrhea and stomatitis, symptomatic treatment drugs corresponding to the symptoms are also often used. The individual symptomatic treatments selected for these uremic symptoms are also the same as in the case of human patients with uremia. There is a difference in drug metabolism between cats and humans. For example, acetaminophen which can be safely used in humans induces a serious side effect (acetaminophen poisoning) in cats. In addition to this, a number of antibiotics and anti-inflammatory agents are listed as drugs requiring caution. Further, since the homeostatic functions in the cats showing uremic symptoms are deteriorated, much caution and care are needed for the usage and dosage of the drugs.
Similar to humans, active carbon preparation is used for the therapy of uremia in cats and dogs. The name of the drug for humans is Kremezin and the name of the animal drug is Covalzin. In this therapy, the preparation is orally administered daily, and the substances causing uremia are made to be adsorbed thereto in the digestive tract, and are excreted together with feces. However, similar to humans, taking is not easy and reduction of appetite and constipation are also induced. Further, there is a concern that useful substances may be removed by the nonspecific adsorption of substances.
Similar to humans, dialysis is a very effective therapy of uremia in cats. However, since it is expensive, the therapy has not prevailed to a general therapy. Although kidney transplantation may also be performed in cats as a curative treatment for chronic renal failure and uremia, this has also scarcely spread because it is expensive.
As described above, uremia of animals and humans are similar in various aspects including the state of disease of chronic renal failure, clinical symptoms of accompanying uremia, therapeutic methods, symptomatic treatments and so on. Further, since there are problems in therapeutic methods as in human, creation of an excellent therapeutic method and therapeutic drug for uremia are demanded by the clients (owner) of the patient animals and veterinarians.
Non-patent Literature 1: Vanholder, R. et al., Kidney International, 63, 1934-1943, 2003
Non-patent Literature 2: Grauer, G. F., PART 5, Chapter 44, Urologic Diseases, p 622, In: Small Animal Internal Medicine (Japanese version), R. W. Nelson, C. G. Couto eds., translation supervised by Atsuhiko HASEGAWA and Hajimu TSUJIMOTO, Inter Zoo Tokyo, 2001Non-patent Literature 3: Yasushi ASANO, VII Chronic Renal Failure, Nephrology (Kiyoshi KUROKAWA eds.), p 345, Nankodo, Tokyo, 2001Non-patent Literature 4: Keizo KOIDE, 1: What is Chronic Renal Failure, Chemotherapies of Chronic Renal Failure (Keizo KOIDE and Susumu TAKAHASHI eds.), p 1, TOKYOIGAKUSHA, Tokyo, 2000Non-patent Literature 5: Utsunomiya, Y. et al., Clin. Exp. Immunol., 99, 454-460, 1995Non-patent Literature 6: Kushiro, M. et al., Kidney International, 53, 1314-1320, 1998Non-patent Literature 7: Stier, C. T. et al., J. Cardiovascular Pharmacology, 30, 285-293, 1997Non-patent Literature 8: Owada, A. et al., Nephron, 92(4):788-796, 2002Non-patent Literature 9: Robles, R. G. et al., J. Hypertens. Suppl., 11, 5:S208-S209, 1993Non-patent Literature 10: Villa, E. et al., Am. J. Hypertens., 6, 253-257, 1993Non-patent Literature 11: Poelstra, K. et al., Am. J. Pathol., 142, 441-450, 1993Non-patent Literature 12: Fujita, T. et al., Prostaglandins Leukot. Essent. Fatty Acids, October; 65(4):223-227. 2001Non-patent Literature 13: Series, C. et al., Rev. Med. Interne., 17, 76-78, 1996Non-patent Literature 14: Siegler, R. L. et al., Nephron, 92, 363-368, 2002Non-patent Literature 15: Mitra, D. et al., Blood, 89, 1224-1234, 1997Non-patent Literature 16: Adler, S. and Bollu, R. Kidney & Blood Pressure Research, 21, 13-21, 1998Non-patent Literature 17: Dibartola, S. P. et al., J. Am. Vet. Med. Assoc., 190, 1196-1202, 1987Non-patent Literature 18: Lulich, J. et al., The Compendium Continuing Education, 14, 127-152, 1992Patent Literature 1: JP 3-163023 APatent Literature 2: JP 1-053672 BPatent Literature 3: WO 00/067748